Novel tricyclic dihydropyrazolone and novel tricyclic dihydroisoxazolone compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions may be treated with therapeutic agents that open potassium channels; see for example (K. Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996)); (D. R. Gehlert et al., Prog. Neuro-Psychopharmacol and Biol. Psychiat., v. 18, pp. 1093-1102 (1994)); (M. Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993)); (J. E. Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996)); (D. E. Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991)); (B. B. Howe et al., J. Pharmacol. Exp. Ther., v. 274 pp. 884890 (1995)); (D. Spanswick et al., Nature, v. 390 pp. 521-25 (Dec. 4, 1997)); (Dompeling Vasa. Supplementum (1992) 3434); (WO9932495); (Grover, J Mol Cell Cardiol. (2000) 32, 677); and (Buchheit, Pulmonary Pharmacology and Therapeutics (1999) 12, 103). Such diseases or conditions include asthma, epilepsy, male sexual dysfunction, female sexual dysfunction, pain, bladder overactivity, stroke, diseases associated with decreased skeletal blood flow such as Raynaud""s phenomenon and intermittent claudication, eating disorders, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery disease, angina and ischemia.
Bladder overactivity is a condition associated with the spontaneous, uncontrolled contractions of the bladder smooth muscle. Bladder overactivity thus is associated with sensations of urgency, urinary incontinence, pollakiuria, bladder instability, nocturia, bladder hyerreflexia, and enuresis (Resnick, The Lancet (1995) 346, 94-99; Hampel, Urology (1997) 50 (Suppl 6A), 4-14; Bosch, BJU International (1999) 83 (Suppl 2), 7-9). Potassium channe openers (KCOs) act as smooth muscle relaxants. Because bladder overactivity and urinary incontinence can result from the spontaneous, uncontrolled contractions of the smooth muscle of the bladder, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, urinary incontinence, and enuresis (Andersson, Urology (1997) 50 (Suppl 6A), 7484; Lawson, Pharmacol. Ther., (1996) 70, 39-63; Nurse., Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp. Ther., (1995) 274, 884-890; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
The irritative symptoms of BPH (urgency, frequency, nocturia and urge incontinence) have been shown to be correlated to bladder instability (Pandita, The J. of Urology (1999) 162, 943). Therefore the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent the symptoms associated with BPH. (Andersson; Prostate (1997) 30: 202-215).
The excitability of corpus cavernosum smooth muscle cells is important in the male erectile process. The relaxation of corporal smooth muscle cells allows arterial blood to build up under pressure in the erectile tissue of the penis leading to erection (Andersson, Pharmacological Reviews (1993) 45, 253). Potassium channels play a significant role in modulating human corporal smooth muscle tone, and thus, erectile capacity. By patch clamp technique, potassium channels have been characterized in human corporal smooth muscle cells (Lee, Int. J. Impot. Res. (1999) 11(4),179-188). Potassium channel openers are smooth muscle relaxants and have been shown to relax corpus cavernosal smooth muscle and induce erections (Andersson, Pharmacological Reviews (1993) 45, 253; Lawson, Pharmacol. Ther., (1996) 70, 39-63, Vick, J. Urol. (2000) 163: 202). Potassium channel openers therefore may have utility in the treatment of male sexual dysfunctions such as male erectile dysfunction, impotence and premature ejaculation.
The sexual response in women is classified into four stages: excitement, plateau, orgasm and resolution. Sexual arousal and excitement increase blood flow to the genital area, and lubrication of the vagina as a result of plasma transudation. Topical application of KCOs like minoxidil and nicorandil have been shown to increase clitoral blood flow (J. J. Kim, J. W. Yu, J. G. Lee, D. G. Moon, xe2x80x9cEffects of topical K-ATP channel opener solution on clitoral blood flowxe2x80x9d, J. Urol. (2000) 163 (4): 240). KCOs may be effective for the treatment of female sexual dysfunction including clitoral erectile insufficiency, vaginismus and vaginal engorgement (I. Goldstein and J. R. Berman., xe2x80x9cVasculogenic female sexual dysfunction: vaginal engorgement and clitoral erectile insufficiency syndromesxe2x80x9d., Int. J. Impotence Res. (1998) 10:S84-S90), as KCOs can increase blood flow to female sexual organs.
Potassium channel openers may have utility as tocolytic agents to inhibit uterine contractions to delay or prevent premature parturition in individuals or to slow or arrest delivery for brief periods to undertake other therapeutic measures (Sanborn, Semin. Perinatol. (1995) 19, 31-40; Morrison, Am. J. Obstet. Gynecol. (1993) 169(5), 1277-85). Potassium channel openers also inhibit contractile responses of human uterus and intrauterine vasculature. This combined effect would suggest the potential use of KCOs for dysmenhorrea (Kostrzewska, Acta Obstet. Gynecol. Scand. (1996) 75(10), 886-91). Potassium channel openers relax uterine smooth muscle and intrauterine vasculature and therefore may have utility in the treatment of premature labor and dysmenorrhoea (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax gastrointestinal smooth tissues and therefore may be useful in the treatment of functional bowel disorders such as irritable bowel syndrome (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax airway smooth muscle and induce bronchodilation. Therefore potassium channel openers may be useful in the treatment of asthma and airways hyperreactivity (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit, Pulmonary Pharmacology and Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Neuronal hyperpolarization can produce analgesic effects. The opening of potassium channels by potassium channel openers and resultant hyperpolarization in the membrane of target neurons is a key mechanism in the effect of opioids. The peripheral antinociceptive effect of morphine results from activation of ATP-sensitive potassium channels, which causes hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation (Rodrigues, Br J Pharmacol (2000) 129(1), 1104). Opening of KATP channels by potassium channel openers plays an important role in the antinociception mediated by alpha-2 adrenoceptors and mu opioid receptors. KCOs can potentiate the analgesic action of both morphine and dexmedetomidine via an activation of KATP channels at the spinal cord level (Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano, Anesth. Analg. (2000) 90(5), 1146-51). Thus, potassium channel openers can hyperpolarize neuronal cells and have shown analgesic effects. Potassium channel openers therefore may be useful as analgesics in the treatment of various pain states including but not limited to migraine and dyspareunia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., (1994) 18, 1093-1102).
Epilepsy results from the propagation of nonphysiologic electrical impulses. Potassium channel openers hyperpolarize neuronal cells and lead to a decrease in cellular excitability and have demonstrated antiepileptic effects. Therefore potassium channel openers may be useful in the treatment of epilepsy (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., (1994) 18, 1093-1102).
Neuronal cell depolarization can lead to excitotoxicity and neuronal cell death. When this occurs as a result of acute ischemic conditions, it can lead to stroke. Long-term neurodegeneration can bring about conditions such as Alzheimer""s and Parkinson""s diseases. Potassium channel openers can hyperpolarize neuronal cells and lead to a decrease in cellular excitability. Activation of potassium channels has been shown to enhance neuronal survival. Therefore potassium channel openers may have utility as neuroprotectants in the treatment of neurodegenerative conditions and diseases such as cerebral ischemia, stroke, Alzheimer""s disease and Parkinson""s disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol and Biol. Psychiat., (1994) 18, 1093-1102; Freedman, The Neuroscientist (1996) 2, 145).
Potassium channel openers may have utility in the treatment of diseases or conditions associated with decreased skeletal muscle blood flow such as Raynaud""s syndrome and intermittent claudication (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Dompeling Vasa. Supplementum (1992) 3434; and WO9932495).
Potassium channel openers may be useful in the treatment of eating disorders such as obesity (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996) 2, 145).
Potassium channel openers have been shown to promote hair growth therefore potassium channel openers have utility in the treatment of hair loss and baldness also known as alopecia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Potassium channel openers possess cardioprotective effects against myocardial injury during ischemia and reperfusion. (Garlid, Circ. Res. (1997) 81(6), 1072-82). Therefore, potassium channel openers may be useful in the treatment of heart diseases (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Grover, J. Mol. Cell Cardiol. (2000) 32, 677).
Potassium channel openers, by hyperpolarization of smooth muscle membranes, can exert vasodilation of the collateral circulation of the coronary vasculature leading to increase blood flow to ischemic areas and could be useful for the coronary artery disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63, Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
U.S. Pat. No. 4,883,872 discloses bicyclic triazolopyrimidines. EP 0299727 A1, WO 90/12015, and JP 2040385 disclose bicyclic pyrazolodihydropyridines. Khim. Geterotsikl. Soedin. (1974) 6, 823-7 discloses tricyclic 4-substituted-1,2,6,7-tetrahydrodipyrazolo[3,4-b:4,3-e]pyridine-3,5-diones. Khim. Geterotsikl. Soedin. (1992) 9, 1218-22 discloses 4-phenyl-1H-furo[3,4-b]pyrazolo[4,3-e]pyridine-3,5(2H,7H)-dione.
The compounds of the present invention are novel, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions, and are useful for treating diseases that can be ameliorated by opening potassium channels.
In its principle embodiment, the present invention discloses compounds of formula I: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
m is an integer 1-2;
n is an integer 0-1;
provided that when m is 2, n is 0;
R1 is selected from the group consisting of aryl and heterocycle;
Q is selected from the group consisting of C(O), S(O), and S(O)2;
V is selected from the group consisting of C(R2)(R3), O, S, and NR4;
R2 and R3 are independently absent or selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR5R6, and (NR5R6)alkyl;
R4 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR5R6, and (NR5R6)alkyl;
R5 and R6 are independently selected from the group consisting of hydrogen and lower alkyl;
X is selected from the group consisting of O and N;
A is absent or selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR5R6, and (NR5R6)alkyl;
B is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, haloalkylcarbonyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR5R6, and (NR5R6)alkyl;
or X is N and A and B together with the nitrogen atoms to which they are attached form a 5 or 6 membered ring; and
D and E are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR5R6, and (NR5R6)alkyl;
provided that when Q is S(O) or S(O)2 and n is 0, then V is C(R2)(R3).
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
In its principle embodiment, the present invention discloses compounds of formula I: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
m is an integer 1-2;
n is an integer 0-1;
provided that when m is 2, n is 0;
R1 is selected from the group consisting of aryl and heterocycle;
Q is selected from the group consisting of C(O), S(O), and S(O)2;
V is selected from the group consisting of C(R2)(R3), O, S, and NR4;
R2 and R3 are independently absent or selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR5R6, and (NR5R6)alkyl;
R4 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR5R6, and (NR5R6)alkyl;
R5 and R6 are independently selected from the group consisting of hydrogen and lower alkyl;
X is selected from the group consisting of O and N;
A is absent or selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR5R6, and (NR5R6)alkyl;
B is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, haloalkylcarbonyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR5R6, and (NR5R6)alkyl;
or X is N and A and B together with the nitrogen atoms to which they are attached form a 5 or 6 membered ring; and
D and E are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR5R6, and (NR5R6)alkyl;
provided that when Q is S(O) or S(O)2 and n is 0, then V is C(R2)(R3).
In a preferred embodiment, compounds of the present invention have formula II: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein R1, V, X, A, B, D, and E are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein V is selected from O and C(R2)(R3); R2 and R3 are independently selected from hydrogen and alkyl; A is absent or selected from hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, and aryl; B is selected from hydrogen, alkyl, and heterocycle; D and E are independently selected from hydrogen and alkyl; and R1 and X are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein V is C(R2)(R3); and R1, R2, R3, A, B, D, E, and X are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein X is N; V is C(R2)(R3); A is selected from hydrogen, alkyl, alkylcarbonyl, and alkoxycarbonyl; R2, R3, B, D, and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein X is N; V is C(R2)(R3); A is selected from hydrogen, alkyl, alkylcarbonyl, and alkoxycarbonyl; R2, R3, D, and E are hydrogen; B is alkyl; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein X is N; V is C(R2)(R3); A is selected from hydrogen, alkyl, alkylcarbonyl, and alkoxycarbonyl; R2, R3, and B are alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein X is O; V is C(R2)(R3); A is absent; B is alkyl; D, E, R2 and R3 are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein X is O; V is C(R2)(R3); A is absent; R2, R3, and B are alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein V is O; and R1, A, B, D, E, and X are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein X is N; V is O; A is selected from hydrogen, alkyl, alkylcarbonyl, and alkoxycarbonyl; B is alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein R1, Q, V, X, A, B, D, and E are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III wherein Q is C(O); V is O; and R1, A, B, D, E, and X are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III wherein X is N; Q is C(O); V is O; A is selected from hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, and aryl; B is selected from hydrogen, alkyl, and heterocycle; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III wherein X is N; Q is C(O); V is O; A is selected from hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, and aryl; B is alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III wherein X is N; Q is C(O); V is O; A is selected from hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, and aryl; B and D are alkyl; E is selected from hydrogen and alkyl; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III wherein X is O; Q is C(O); V is O; A is absent; B is alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein R1, V, X, A, B, D, and E are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein V is selected from O and C(R2)(R3); R2 and R3 are independently selected from hydrogen and alkyl; A is absent or selected from hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, and aryl; B is selected from hydrogen, alkyl, and heterocycle; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein V is C(R2)(R3); and R1, R2, R3, X, A, B, D, and E are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein X is N; V is C(R2)(R3); R2 and R3 are hydrogen; A is hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, and aryl wherein aryl is phenyl; B, D, and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein X is N; V is C(R2)(R3); R2 and R3 are hydrogen; A is hydrogen, alkyl, alkylcarbonyl, and alkoxycarbonyl; B is alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein X is N; V is C(R2)(R3); R2 and R3 are hydrogen; A is hydrogen, alkyl, alkylcarbonyl, and alkoxycarbonyl; B is heterocycle wherein heterocycle is pyridinyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein X is O; V is C(R2)(R3); R2 and R3 are hydrogen; A is absent; B is alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein V is O; and R1, X, A, B, D, and E are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein X is N; V is O; A is hydrogen, alkyl, alkylcarbonyl, and alkoxycarbonyl; B is alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein X is O; V is O; A is absent; B is alkyl; D and E are hydrogen; and R1 is as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula V: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein p is an integer 1-2; and R1, R2, R3, X, A, B, D, and E are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula V wherein p is an integer 1-2; R2 and R3 are independently selected from hydrogen and alkyl; A is absent or selected from hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, and aryl; B is selected from hydrogen, alkyl, and heterocycle; D and E are hydrogen; and R1 and X are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula V wherein p is an integer 1-2; X is N; R2 and R3 are hydrogen; A is selected from hydrogen, alkyl, alkylcarbonyl, and alkoxycarbonyl; B is alkyl; D and E are hydrogen; and R1 is as defined in formula I.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I-V or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of treating male sexual dysfunction including, but not limited to, male erectile dysfunction and premature ejaculation, comprising administering a therapeutically effective amount of a compound of formula I-V or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the invention relates to a method of treating female sexual dysfunction including, but not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal engorgement, dyspareunia, and vaginismus comprising administering a therapeutically effective amount of a compound of formula I-V or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Yet another embodiment of the invention relates to a method of treating asthma, epilepsy, Raynaud""s syndrome, intermittent claudication, migraine, pain, bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, eating disorders, urinary incontinence, enuresis, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, and ischemia comprising administering a therapeutically effective amount of a compound of formula I-V or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
As used throughout this specification and the appended claims, the following terms have the following meanings.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of xe2x80x9calkenylxe2x80x9d include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl and the like.
The term xe2x80x9calkenyloxy,xe2x80x9d as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkenyloxy include, but are not limited to, propen-3-yloxy (allyloxy), buten-4-yloxy, and the like.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
The term xe2x80x9calkylcarbonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.
The term xe2x80x9calkylcarbonyloxy,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited, methylsulfinyl, ethylsulfinyl, and the like.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited, methylsulfonyl, ethylsulfonyl, and the like.
The term xe2x80x9calkylthio,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
The aryl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, aryloxy, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, sulfamyl, sulfo, sulfonate, xe2x80x94NR80R81 (wherein, R80 and R81, are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and xe2x80x94C(O)NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl).
The term xe2x80x9carylalkenyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3-phenylpropen-2-yl, 2-naphth-2-ylethenyl, and the like.
The term xe2x80x9carylalkoxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
The term xe2x80x9carylalkoxycarbonyl,xe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, and the like.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a xe2x80x94CO2H group.
The term xe2x80x9ccarboxy protecting group,xe2x80x9d as used herein, refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy-protecting groups are disclosed in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York (1999), which is hereby incorporated herein by reference. In addition, a carboxy-protecting group can be used as a prodrug whereby the carboxy-protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in xe2x80x9cPro-drugs as Novel Delivery Systemsxe2x80x9d, Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy-protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of xe2x80x9cBioreversible Carriers in Drug Design: Theory and Applicationxe2x80x9d, edited by E. B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy-protecting groups are loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); benzyl (phenylmethyl) and substituted benzyl derivatives thereof such substituents are selected from alkoxy, alkyl, halogen, and nitro groups and the like.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl, and the like.
The term xe2x80x9cformyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)H group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
The term xe2x80x9chaloalkoxy,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, 2-chloroethoxy, difluoromethoxy, 1,2-difluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, and the like.
The term xe2x80x9cheterocycle,xe2x80x9d as used herein, refers to a monocyclic- or a bicyclic-ring system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazoie, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like.
The heterocycle groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkoxycarbonyl, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, phenyl, sulfamyl, sulfo, sulfonate, xe2x80x94NR80R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and xe2x80x94C(O)NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, aryl, and arylalkyl).
The term xe2x80x9cheterocyclealkyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl, and the like.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to an xe2x80x94OH group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.
The term xe2x80x9clower alkyl,xe2x80x9d as used herein, is a subset of alkyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
The term xe2x80x9cmercapto,xe2x80x9d as used herein, refers to a xe2x80x94SH group.
The term xe2x80x9c(NR5R6)alkyl,xe2x80x9d as used herein, refers to a xe2x80x94NR5R6 group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NR5R6)alkyl include, but are not limited to, aminomethyl, dimethylaminomethyl, 2-(amino)ethyl, 2-(dimethylamino)ethyl, and the like.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9cnitrogen protecting groupxe2x80x9d or xe2x80x9cN-protecting group,xe2x80x9d as used herein, refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures. N-protecting groups comprise carbamates, amides, N-benzyl derivatives, and imine derivatives. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, triphenylmethyl (trityl), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz). Commonly used N-protecting groups are disclosed in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York (1999).
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to a xe2x95x90O moiety.
The term xe2x80x9coxy,xe2x80x9d as used herein, refers to a xe2x80x94Oxe2x80x94 moiety.
The term xe2x80x9csulfamyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2NR94R95 group, wherein, R94 and R95 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, refers to a xe2x80x94S(O)xe2x80x94 group.
The term xe2x80x9csulfo,xe2x80x9d as used herein, refers to a xe2x80x94SO3H group.
The term xe2x80x9csulfonate,xe2x80x9d as used herein, refers to a xe2x80x94S(O)2OR96 group, wherein, R96 is selected from alkyl, aryl, and arylalkyl, as defined herein.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9cthio,xe2x80x9d as used herein, refers to a xe2x80x94Sxe2x80x94 moiety.
The following preferred compounds may be prepared by one skilled in the art using using methodology described in the Schemes and Examples contained herein or by using methods known to those of skill in the art.
4-(3-bromo-4-fluorophenyl)-1-ethyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1-propyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1-butyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1-isobutyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1-isopropyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
1-methyl-4-[4-(trifluoromethoxy)phenyl]-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
1-methyl-4-[4-(trifluoromethoxy)phenyl]-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
1-methyl-4-[4-(trifluoromethoxy)phenyl]-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
4-(4-chloro-3-nitrophenyl)-1-methyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
4-(4-chloro-3-nitrophenyl)-1-methyl-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
4-(3,4-dichlorophenyl)-1-methyl-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
4-(3,4-dichlorophenyl)-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3,4-dichlorophenyl)-1-methyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
4-(4-fluoro-3-iodophenyl)-1-methyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
4-(4-fluoro-3-iodophenyl)-1-methyl-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
3-(1-methyl-3,5-dioxo-3,4,5,6,7,8-hexahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridin-4-yl)benzonitrile;
3-(1-methyl-3,5-dioxo-1,3,4,5,6,7,8,9-octahydroisoxazolo[3,4-b]quinolin-4-yl)benzonitrile;
4-(3-bromo-4-methylphenyl)-1-methyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
4-(3-bromo-4-methylphenyl)-1-methyl-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
4-(4-bromo-3-chlorophenyl)-1-methyl-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
4-(4-bromo-3-chlorophenyl)-1-methyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione; and
4-(4-bromo-3-chlorophenyl)-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione.
4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,8-dihydro-1H,3H-furo[3,4-b]isoxazolo[4,3-e]pyridine-3,5(7H)-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,6,7,8-tetrahydro-1H-isoxazolo[3,4-b]pyrrolo[3,4-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,7,8,9-tetrahydro-3H-isoxazolo[3,4-b]pyrano[3,4-e]pyridine-3,5(1H)-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,6,7,8-tetrahydroisoxazolo[3,4-b]thieno[2,3-e]pyridin-3(1H)-one 5,5-dioxide;
4-phenyl-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano [3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1,2,6,6-tetramethyl-1,2,4,9-tetrahydropyrano [3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
2-acetyl-4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-2-(methoxycarbonyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-[4-(trifluoromethoxy)phenyl]-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano [3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-methylphenyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano [3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(4-chloro-3-nitrophenyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano [3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-iodo-4-methylphenyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(4-fluoro-3-iodophenyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3,4-dichlorophenyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-[4-fluoro-3-(2-furyl)phenyl]-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(5-nitro-3-thienyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(2,1,3-benzoxadiazol-5-yl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano [3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(2,1,3-benzothiadiazol-5-yl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(4-bromo-3-chloro)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
1,6,6-trimethyl-4-phenyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1,2,6,6-tetramethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
2-acetyl-4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-2-(methoxycarbonyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-[4-(trifluoromethoxy)phenyl]-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-methylphenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(4-chloro-3-nitrophenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-iodo-4-methylphenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(4-fluoro-3-iodophenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3,4-dichlorophenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(4-fluoro-3-(2-furyl)phenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(5-nitro-3-thienyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(2,1,3-benzoxadiazol-5-yl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(2,1,3-benzthiadiazol-5-yl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione; and
4-(4-bromo-3-chlorophenyl)-1,6,6-trimethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione.
Most preferred compounds of the present invention include:
4-(3-bromo-4-fluorophenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
4-(3-bromo-4-fluorophenyl)-1-ethyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1-tert-butyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1-(2-pyridinyl)-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
1-methyl-4-[4-(trifluoromethoxy)phenyl]-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-methylphenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(4-chloro-3-nitrophenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-iodo-4-methylphenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(4-fluoro-3-iodophenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3,4-dichlorophenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-[4-fluoro-3-(2-furyl)phenyl]-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
1-methyl-4-(5-nitro-3-thienyl)-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(2,1,3-benzoxadiazol-5-yl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(2,1,3-benzothiadiazol-5-yl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
4-(3-bromo-4-fluorophenyl)-2-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-2-phenyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-1,2,4,6,7,8-hexahydro-3H-pyrazolo[3,4-b]thieno[2,3-e]pyridin-3-one 5,5-dioxide;
4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
4-(4-fluoro-3-iodophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
4-(3,4-dichlorophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
4-[4-fluoro-3-(2-furyl)phenyl]-1,6,6-trimethyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1-ethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(4-fluoro-3-iodophenyl)-1-methyl-1,2,4,9-tetrahydropyrano [3,4-b]pyrazolo [4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-iodo-4-methylphenyl)-1-methyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(4-bromo-3-chlorophenyl)-1-methyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-1,2,4,7,8,9-hexahydropyrano[4,3-b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,8-dihydro-1H-furo[3,4-b]pyrazolo[4,3-e]pyridine-3,5(2H,7H)-dione;
(+) 4-(3-bromo-4-fluorophenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
(xe2x88x92) 4-(3-bromo-4-fluorophenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
2-acetyl-4-(3-bromo-4-fluorophenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
(xe2x88x92) 4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
(+) 4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
2-acetyl-4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
4-(3-bromo-4-fluorophenyl)-2-(methoxycarbonyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(4-bromo-3-chlorophenyl)-1-methyl-1,2,4,6,7,8-hexahydrocyclopenta[b]pyrazolo[4,3-e]pyridine-3,5-dione;
4-(4-bromo-3-chlorophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione;
2-acetyl-4-(3-bromo-4-fluorophenyl)-1-methyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1,6-dimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-fluorophenyl)-1,6,6-trimethyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,8-dihydro-1H,3H-furo[3,4-b]isoxazolo[4,3-e]pyridine-3,5(7H)-dione;
4-(3-bromo-4-fluorophenyl)-1,2-dimethyl-1,2,4,9-tetrahydropyrano[3,4-b]pyrazolo[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(3-bromo-4-methylphenyl)-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(2,1,3-benzoxadiazol-5-yl)-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
4-(4-chloro-3-nitrophenyl)-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
3-(1-methyl-3,5-dioxo-3,4,5,6,8,9-hexahydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridin-4-yl)benzonitrile;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,6,7,8-tetrahydro-1H-cyclopenta[b]isoxazolo[4,3-e]pyridine-3,5-dione;
4-(3-bromo-4-fluorophenyl)-1-methyl-4,7,8,9-tetrahydroisoxazolo[3,4-b]quinoline-3,5(1H,6H)-dione;
4-(4-fluoro-3-iodophenyl)-1-methyl-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione;
1-methyl-4-(5-nitro-3-thienyl)-4,9-dihydro-1H-isoxazolo[3,4-b]pyrano[4,3-e]pyridine-3,5(6H,8H)-dione and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: AcOH for acetic acid, Ac2O for acetic anhydride, AIBN for 2,2xe2x80x2-azobis(2-methylpropionitrile), DMF for N,N-dimethylformamide, EtOAc for ethyl acetate, EtOH for ethanol, MeOH for methanol, Ms for mesylate or xe2x80x94OS(O)2CH3, THF for tetrahydrofuran, and Ts for tosylate or xe2x80x94OS(O)2-(para-CH3Ph).
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-28. 
5-Amino-3-pyrazolones of general formula (1) or (2), wherein A and B are as defined in formula I, can be prepared as described in Scheme 1. Ethyl cyanoacetate can be treated with hydrazine (A and B are hydrogen), monosubstituted hydrazines (A is hydrogen or B is hydrogen), or 1,2-disubstituted hydrazines (A and B are other than hydrogen) to provide 5-amino-3-pyrazolones of general formula (1) or (2), depending on the A and B substituents. In the cases where both regioisomers are formed, as shown, chromatography can be used to separate isomers (1) from (2). 
Alternatively, 1,2-disubstituted pyrazolones of general formula (1), wherein A and B are as defined in formula I, may be prepared as described in Scheme 2. Monosubstituted pyrazolones of general formula (3) can be treated with an appropriate nitrogen protecting reagent such as di-tert-butyl dicarbonate to provide 5-aminoprotected pyrazolones. 5-Aminoprotected pyrazolones can be alkylated or acylated to provide 1,2-disubstituted-5-aminoprotected pyrazolones. 5-Aminoprotected pyrazolones can be deprotected to provide 1,2-disubstituted-5-amino-3-pyrazolones of general formula (1). 
3-Amino-5(2H)-isoxazolones of general formula (5), wherein B is as defined in formula I, can be prepared as described in Scheme 3. Ethyl cyanoacetate can be treated with hydroxylamines of general formula (4) as described in (Bauer, L., Nambury, C. N. V., and Bell, C. L., Tetrahedron (1964) 20, 165-171; and Barbieri, W., et al. Tetrahedron (1967) 23, 4395-4406) to provide 3-amino-5(2H)-isoxazolones of general formula (5). 
Dihydropyridines of general formula (9), wherein R1, A, B, D, E, V, and X are as defined in formula I, can be prepared according to the method of Scheme 4. Dicarbonyl compounds of general formula (6) can be treated with aldehydes of general formula (7) and amino heterocycles of general formula (8), prepared as described in Schemes 1, 2, and 3 in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide dihydropyridines of general formula (9). An additional heating step, with an acid such as HCl, may be required to drive the reaction to completion. Dicarbonyl compounds of general formula (6) may be prepared as described in (Nakagawa, S., Heterocycles 13 (1979) 477; and D""Angelo, J., Tetrahedron Letters 32 (1991) 3063). 
Dihydropyridines of general formula (13), wherein R1, R2, R3, A, B, D, E, V, and X are as defined in formula 1, can be prepared according to the method of Scheme 5. Dicarbonyl compounds of general formula (12), prepared as described in Scheme 6, can be treated with aldehydes of general formula (7) and amino heterocycles of general formula (8), prepared as described in Schemes 1, 2, and 3 in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide dihydropyridines of general formula (13). An additional heating step, with an acid such as HCl, may be required to drive the reaction to completion. 
Dicarbonyl compounds of general formula (12), wherein R2, R3, and V are as defined in formula I, can be prepared as described in Scheme 6. Esters of general formula (15), wherein V is selected from S or NR4 and R4 is as defined in formula I, can be alkylated with chloroacetone to provide ketoesters of general formula (17). Ketoesters of general formula (17) can cyclize in the presence of a base such as potassium tert-butoxide to provide dicarbonyl compounds of general formula (12). An alternative method of preparing ketoesters of general formula (17) can also be used. Acid chlorides of general formula (16), wherein V is O, prepared as described in (Terasawa, J. Org. Chem. (1977), 42, 1163-1169) can be treated with dimethyl zinc in the presence of a palladium catalyst to provide ketoesters of general formula (17).
An alternative method of preparing dicarbonyl compounds of general formula (12) can be used as described in Scheme 6. Alkynes of general formula (18) can be treated with methyl bromoacetate to provide ethers of general formula (19). A base such as sodium hydride may be necessary when V is O or S. Ethers of general formula (19) can be treated with a catalyst such as mercuric acetate in the presence of a catalytic amount of sulfuric acid with heating in a solvent such as methanol followed by treatment with aqueous acid to provide methyl ketones of general formula (19A). Methyl ketones of general formula (19A) can be treated with a strong base such as potassium tert-butoxide to provide dicarbonyl compounds of general formula (12).
Alkynes of general formula (18), wherein V=O, can be purchased or prepared by reaction of a nucleophilic source of acetylene such a ethynylmagnesium bromide with an appropriate ketone or aldehyde.
Chiral alkynes of general formula (18), wherein V=O, can also be purchased or generated by known methods (Midland, M. Tetrahedron (1984), 40, 1371-1380; Smith, R. J.Med.Chem. (1988), 31, 1558-1566) and then processed to provide chiral dicarbonyl compounds of general formula (12).
Dicarbonyl compounds of general formula (12) may also be prepared using the procedures described in (Ziegler, J. Amer. Chem. Soc. (1973), 95, 7458-7464; and Terasawa, T., Journal of Organic Chemistry 42 (1977) 1163). 
Dihydropyridines of general formula (23), wherein R1, R2, R3, A, B, and X are as defined in formula I, can be prepared according to the method of Scheme 7. Dicarbonyl compounds of general formula (22) can be prepared as described in (Suihara, Y. Et al, JACS (1985) 107, 5894-5897). Ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate can be treated with a strong base such as lithium diisopropylamine and an electrophile to provide esters of general formula (20). Esters of general formula (20) can be treated again with the same alkylating conditions to provide esters of general formula (20A). Esters (20) or (20A) can be hydrolized under mild acid conditions and the resultant keto ester treated with strong base such as lithium diisopropylamine to provide dicarbonyl compounds of general formula (22). Dicarbonyl compounds of general formula (22) can be treated with aldehydes of general formula (7) and amino heterocycles of general formula (8), prepared as described in Schemes 1, 2, and 3 in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide dihydropyridines of general formula (23). 
Dihydropyridines of general formula (28) and (29), wherein A, B, X, R1, and R4 are as defined in formula I, can be prepared as described in Scheme 8. Methyl acetoacetate can be condensed with aldehydes (7) to provide xcex1,xcex2-unsaturated ketones of general formula (24). xcex1,xcex2-Unsaturated ketones of general formula (24) can be treated with amino heterocycles of general formula (8), prepared as described in Schemes 1, 2, and 3 to provide dihydropyridines of general formula (25). Dihydropyridines of general formula (25) can be treated with brominating agents such as N-bromosuccinimide or pyridinium tribromide in a solvent such as methanol, ethanol, isopropanol, or chloroform to provide dihydropyridines of general formula (26). Dihydropyridines of general formula (26) can be treated with primary amines of general formula (27) or ammonia with heat in a solvent such as ethanol to provide dihydropyridines of general formula (28). Dihydropyridines of general formula (26) can be heated neat or in a solvent such as chloroform to provide dihydropyridines of general formula (29).
An alternative and more preferred method of preparing dihydropyridines of general formula (29) can be used as described in Scheme 8. Ethyl 4(acetyloxy)-3-oxobutanoate prepared as described in (S. Husband, W. Fraser, C. J. Suckling, H. C. Wood, Tetrahedron, (1995) 51(3), 865), can be treated with aldehydes of general formula (7) and amino heterocycles of general formula (8) with heat in an alcoholic solvent such as ethanol to provide dihydropyridines of general formula (30). Dihydropyridines of general formula (30) can be treated with potassium carbonate in methanol to provide dihydropyridines of general formula (29). 
Dihydropyridines of general formula (36), wherein A, B, X, R2, R3, and m are as defined in formula I, can be prepared as described in Scheme 9. xcex2-Keto sulfides of general formula (32) can be treated with secondary amines such as morpholine, pyrrolidine or piperidine to provide enamines of general formula (33) which can be condensed with aldehydes (7) in an appropriate organic solvent to provide sulfides of general formula (34). Sulfides of general formula (34) can be oxidized with an oxidant such as meta-chloroperoxybenzoic acid to sulfoxides of general formula (35). Sulfoxides of general formula (35) can be treated with amino heterocycles of general formula (8), prepared as described in Schemes 1, 2, and 3 with heating in a solvent such as ethyl alcohol or similar alcoholic solvent, acetonitrile or dimethylformamide to provide dihydropyridines of general formula (36). 
Dihydropyridines of general formula (38), wherein R1, R2, R3, A, B, and m are as defined in formula I, can be prepared according to the method of Scheme 10. Ketosulfones of general formula (41), prepared as described in Scheme 11, can be treated with aldehydes of general formula (7) and amino heterocycles of general formula (8), prepared as described in Schemes 1, 2, and 3 in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide dihydropyridines of general formula (38). 
Ketosulfones of general formula (41), wherein R2, R3, and m are as defined in formula I, can be prepared as described in Scheme 11. Reduction of ketone (32) with sodium borohydride (or the like) in a solvent such as ethanol provides alcohols of general formula (39) which can be oxidized to the corresponding sulfones of general formula (40) using an oxidizing agent such as hydrogen peroxide catalyzed by sodium tungstate. Further oxidation of (40) using Jones reagent or the like provides ketosulfones of general formula (41).
Many of the starting aryl and heteroaryl aldehydes necessary to carry out the methods described in the preceeding and following Schemes may be purchased from commercial sources or may be synthesized by known procedures found in the chemical literature. Appropriate literature references for the preparation of aryl and heteroaryl aldehydes may be found in the following section or in the Examples. For starting materials not previously described in the literature the following Schemes are intended to illustrate their preparation through a general method.
The preparation of aldehydes used to synthesize many preferred compounds of the invention may be found in the following literature references: Pearson, Org. Synth. Coll. Vol V (1973), 117; Nwaukwa, Tetrahedron Lett. (1982), 23, 3131; Badder, J. Indian Chem. Soc. (1976), 53, 1053; Khanna, J. Med. Chem. (1997), 40, 1634; Rinkes, Recl. Trav. Chim. Pays-Bas (1945), 64, 205; van der Lee, Recl. Trav. Chim. Pays43 as (1926), 45, 687; Widman, Chem. Ber. (1882), 15, 167; Hodgson, J. Chem. Soc. (1927), 2425; Clark, J. Fluorine Chem. (1990), 50, 411; Hodgson, J. Chem. Soc. (1929), 1635; Duff, J. Chem. Soc. (1951), 1512; Crawford, J. Chem. Soc. (1956), 2155; Tanouchi, J. Med. Chem. (1981), 24, 1149; Bergmann, J. Am. Chem. Soc. (1959), 81, 5641; Other: Eistert, Chem. Ber. (1964), 97, 1470; Sekikawa, Bull. Chem. Soc. Jpn. (1959), 32, 551. 
Meta, para-disubstituted aldehydes of general formula (81), wherein R10 is selected from alkyl, haloalkyl, halogen, haloalkoxy, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halogen, and alkylcarbonyl, can be prepared according to the method described in Scheme 12. A para substituted aldehyde of general formula (80) or the corresponding acetal protected aldehyde of general formula (82), wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, may by subjected to conditions of an electrophilic aromatic substitution reaction to provide aldehydes of general formula (81) or protected aldehydes of general formula (83). Preferred protecting groups for compounds of general formula (82) and (83) include dimethyl or diethyl acetals or the 1,3-dioxolanes. These protecting groups can be introduced at the beginning and removed at the end to provide substituted aldehydes of general formula (81) using methods well known to those skilled in the art of organic chemistry. 
Aldehydes of general formula (88), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halogen, and alkylcarbonyl, can be prepared by the method described in Scheme 13. A meta substituted phenol (86) is converted to the para substituted salicylaldehyde (87) by reaction with a base such as sodium hydroxide and a reagent such as trichloromethane or tribromomethane, known as the Reimer-Tiemann reaction. An alternate set of reaction conditions involves reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). The aldehyde (87) may be subjected to conditions of an electrophilic aromatic substitution reaction to provide meta, para disubstituted salicylaldehydes of general formula (88). 
An alternative method of preparing meta, para disubstituted salicylaldehydes of general formula (88), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo, and alkylcarbonyl, can be used as described in Scheme 14. A meta, para disubstituted phenol of general formula (89) can be reacted with a base such as sodium hydroxide and a reagent such as trichloromethane or tribromomethane, known as the Reimer-Tiemann reaction, to provide disubstituted salicylaldehydes of general formula (88). An alternate set of reaction conditions involves reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). 
An alternative method of preparing benzaldehydes of general formula (81), wherein R12 is selected from alkyl, haloalkyl, chlorine, fluorine, haloalkoxy, alkoxy, alkylthio, nitro, alkylcarbonyl, arylcarbonyl, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R10 is selected from alkyl, hydroxyalkyl, alkylthio, alkylcarbonyl, and formyl, is described in Scheme 15. Protected benzaldehydes of general formula (90), wherein Y is selected from bromine or iodine and wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, can be converted to 3,4-disubstituted protected benzaldehydes of general formula (83) via conversion to an intermediate lithio or magnesio derivative, followed by reaction with an appropriate electrophile such as an aldehyde, dialkyldisulfide, a Weinreb amide, dimethylformamide, an alkyl halide or other electrophile followed by deprotection of the acetal to provide benzaldehydes of general formula (81).
An alternative method of preparing benzaldehydes of general formula (81), wherein R12 is selected from alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R10 is selected from alkyl, alkynyl, vinyl, aryl, heteroaryl, cyano and the like, is also described in Scheme 15. Protected benzaldehydes of general formula (90), wherein Y is selected from bromine, iodine, or triflate, and wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, can be treated with suitable tin, boronic acid, alkyne, or unsaturated halide reagents in the presence of a catalyst such as a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides protected benzaldehydes of general formula (83). Deprotection of the acetal of general formula (83) provides benzaldehydes of general formula (81). 
An alternative method of preparing benzaldehydes of general formula (81), wherein R10 is selected from alkyl, haloalkyl, chlorine, fluorine, haloalkoxy, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R12 is selected from alkyl, hydroxyalkyl, alkylthio, alkylcarbonyl, arylcarbonyl, and formyl, can be used as described in Scheme 16. Protected benzaldehydes of general formula (92), wherein Y is selected from bromine or iodine, and wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred can be converted to 3,4-disubstituted protected benzaldehydes of general formula (83) via conversion to an intermediate lithio or magnesio derivative, followed by reaction with an appropriate electrophile such as an aldehyde, dialkyldisulfide, a Weinreb amide, dimethylformamide, an alkyl halide or other electrophile followed by deprotection of the acetal to provide benzaldehydes of general formula (81).
An alternative method of preparing benzaldehydes of general formula (81), wherein R10 is selected from alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R12 is selected from alkyl, alkynyl, vinyl, aryl, heteroaryl, cyano and the like, is also described in Scheme 16. Protected benzaldehydes of general formula (92), wherein Y is selected from bromine, iodine, or triflate, and wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, can be treated with suitable tin, boronic acid, alkyne, or unsaturated halide reagents in the presence of a catalyst such as a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides protected benzaldehydes of general formula (83). Deprotection of the acetals of general formula (83) provides benzaldehydes of general formula (81). 
Benzaldehydes of general formula (95), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R13 is selected from alkyl, arylalkyl, and haloalkyl wherein preferred haloalkyl groups are selected from difluoromethyl, 2,2,2-trifluoroethyl and bromodifluoromethyl, can be prepared as described in Scheme 17. 3-Hydroxybenzaldehyde of general formula (94) can be treated with suitable alkylating reagents such as benzylbromide, iodomethane, 2-iodo-1,1,1-trifluoroethane, chlorodifluoromethane, or dibromodifluoromethane in the presence of base such as potassium carbonate, potassium tert-butoxide or sodium tert-butoxide, to provide benzaldehydes of general formula (95). The synthesis of useful 3-hydroxybenzaldehydes of general formula (94) may be found in the following literature references: J. Chem. Soc. (1923), 2820; J. Med Chem. (1986), 29, 1982; Monatsh. Chem. (1963), 94, 1262; Justus Liebigs Ann. Chem. (1897), 294, 381; J. Chem. Soc. Perkin Trans. 1 (1990), 315; Tetrahedron Lett. (1990), 5495; J. Chem. Soc. Perkin Trans. 1 (1981), 2677. 
Benzaldehydes of general formula (98), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R13 is selected from alkyl, arylalkyl, and haloalkyl wherein preferred haloalkyl groups are selected from difluoromethyl, 2,2,2-trifluoroethyl, and bromodifluoromethyl, can be prepared as described in Scheme 18. 4-Hydroxybenzaldehydes of general formula (97) can be treated with suitable alkylating reagents such as benzylbromide, iodomethane, 2-iodo-1,1,1-trifluoroethane, chlorodifluoromethane, or dibromodifluoromethane, in the presence of base such as potassium carbonate, potassium tert-butoxide or sodium tert-butoxide to provide benzaldehydes of general formula (98). The synthesis of useful 4-hydroxybenzaldehydes of general formula (97) may be found in the following literature references: Angyal, J. Chem. Soc. (1950), 2141; Ginsburg, J. Am. Chem. Soc. (1951), 73, 702; Claisen, Justus Liebigs Ann. Chem. (1913), 401, 107; Nagao, Tetrahedron Lett. (1980), 21, 4931; Ferguson, J. Am. Chem. Soc. (1950), 72, 4324; Barnes, J. Chem. Soc. (1950), 2824; Villagomez-Ibarra, Tetrahedron (1995), 51, 9285; Komiyama, J. Am. Chem. Soc. (1983), 105, 2018; DE 87255; Hodgson, J. Chem. Soc. (1929), 469; Hodgson, J. Chem. Soc. (1929), 1641. 
An alternate method for introduction of substituents at the 3-position of benzaldehydes of general formula (81), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl can be used as described in Scheme 19. This method, also known as the Sandmeyer reaction, involves converting 3-amino benzaldehydes of general formula (100) to an intermediate diazonium salt with sodium nitrite. The diazonium salts can be treated with a bromine or iodine source to provide the bromide or iodide. The Sandmeyer reaction and conditions for effecting the transformation are well known to those skilled in the art of organic chemistry. The types of R12 substituents that may be introduced in this fashion include cyano, hydroxy, or halo. In order to successfully carry out this transformation it may in certain circumstances be advantageous to perform the Sandmeyer reaction on a protected aldehyde.
The resulting iodide or bromide can then be treated with unsaturated halides, boronic acids or tin reagents in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) to provide benzaldehydes of general formula (81). The diazonium salts can also be treated directly with unsaturated halides, boronic acids or tin reagents in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) to provide benzaldehydes of general formula (81). 
An alternate method for introduction of substituents at the 4-position of benzaldehydes of general formula (81), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, can be used as described in Scheme 20. This method, also known as the Sandmeyer reaction, involves converting 4-amino benzaldehydes of general formula (102) to an intermediate diazonium salt with sodium nitrite and then treating the diazonium salts in a similar manner as that described in Scheme 19. The types of R10 substituents that may be introduced in this fashion include cyano, hydroxy, or halo. The Sandmeyer reaction and conditions for effecting the transformation are well known to those skilled in the art of organic chemistry. In order to successfully carry out this transformation it may in certain circumstances be advantageous to perform the Sandmeyer reaction on a protected aldehyde. 
4-Bromo-3-(trifluoromethoxy)benzaldehyde or 4-chloro-3-(trifluoromethoxy)benzaldehyde can be prepared as described in Scheme 21. The commercially available 4-bromo-2-(trifluoromethoxy)aniline can be protected on the amino group with a suitable N-protecting group well known to those skilled in the art of organic chemistry such as acetyl or tert-butoxycarbonyl. The bromine can then be converted to the lithio or magnesio derivative and reacted directly with dimethylformamide to provide the 4-aminoprotected-3-(trifluoromethoxy)benzaldehyde derivative. Removal of the N-protecting group followed by conversion of the amine to a bromide or chloride via the Sandmeyer method of Scheme 19 followed by hydrolysis of the dioxolane provides 4-bromo-3-(trifluoromethoxy)benzaldehyde or 4-chloro-3-(trifluoromethoxy)benzaldehyde. 
4-Trifluoromethylbenzaldehydes of general formula (105), wherein Y is selected from cyano, nitro, and halo may be prepared according to the method of Scheme 22. 4-Trifluoromethylbenzoic acid is first nitrated, using suitable conditions well known in the literature such as nitric acid with sulfuric acid, and the carboxylic acid group reduced with borane to provide 3-nitro-4-trifluoromethylbenzyl alcohol. From this benzyl alcohol may be obtained the 3-nitro-4-trifluoromethylbenzaldehyde by oxidation with typical reagents such as manganese dioxide. The nitro benzylic alcohol can be reduced to the aniline using any of a number of different conditions for effecting this transformation among which a preferred method is hydrogenation over a palladium catalyst. The aniline can be converted to either a halo or cyano substituent using the Sandmeyer reaction described in Scheme 19. Benzyl alcohols of general formula (104) can be oxidized using conditions well known to those skilled in the art such as manganese dioxide or Swern conditions to provide benzaldehydes of general formula (105).
For certain aromatic ring substitutions of R1 for compounds of the present invention it is preferable to effect transformations of the aromatic ring substitutions after the aldehyde has been incorporated into the core structure of the present invention. As such, compounds of the present invention may be further transformed to other distinct compounds of the present invention. These transformations involve Stille, Suzuki and Heck coupling reactions all of which are well known to those skilled in the art of organic chemistry. Shown below are some representative methods of such transformations of compounds of the present invention to other compounds of the present invention. 
Dihydropyridines of general formula (108), wherein Q, V, X, A, B, D, E, n and m are as defined in formula I, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, R12 is selected from alkyl, vinyl, aryl, heteroaryl, cyano and the like, can be prepared as described in Scheme 23. Compounds of general formula (107), wherein Y is selected from bromine, iodine, and triflate, are protected with a tert butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable tin, boronic acid, or unsaturated halide reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (108). The conditions for this transformation also effect the removal of the Boc protecting group. 
Dihydropyridines of general formula (111), wherein Q, V, X, A, B, D, E, n and m are as defined in formula I, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R1, is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, R12 is selected from alkyl, vinyl, aryl, heteroaryl, cyano and the like, can be prepared as described in Scheme 24. Dihydropyridines of general formula (110), wherein Y is selected from bromine, iodine, and triflate, can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be reacted with a suitable tin, boronic acid, or unsaturated halide reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (111). The conditions for this transformation also effect the removal of the Boc protecting group. 
Dihydropyridines of general formula (113), wherein Q, V, X, A, B, D, E, n and m are as defined in formula I, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, can be prepared as described in Scheme 25. Dihydropyridines of general formula (107), wherein Y is selected from bromine, iodine, and triflate can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable halozinc reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (113). The conditions for this transformation also effect the removal of the Boc protecting group. The types of meta substituents that may be introduced in this fashion include trihalopropenyl and more specifically the trifluoropropenyl group. 
Dihydropyridines of general formula (116), wherein Q, V, X, A, B, D, E, n and m are as defined in formula I, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, can be prepared as described in Scheme 26. Dihydropyridines of general formula (110), wherein Y is selected from bromine, iodine, and triflate can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable halozinc reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (116). The conditions for this transformation also effect the removal of the Boc protecting group. The types of para substituents that may be introduced in this fashion include trihalopropenyl and more specifically the trifluoropropenyl group. 
Dihydropyridines of general formula 118, wherein R1, Q, V, B, D, E, m, and n are as defined in formula I provided that B is other than hydrogen, may be separated into individual enantiomers using the procedure described in Scheme 27. Dihydropyridines of general formula (118) can be treated with acetic anhydride (excess) and heat to provide acylated dihydropyridines of general formula (119) and (120). Dihydropyridines of general formula (119) and (120) can be separarted by flash chromatography. Dihydropyridines of general formula (119) can then be subjected to chiral column chromatography to provide enantiomers of general formula (121) and (122). Enantiomers of general formula (121) and (122) can be treated with 6N HCl in methanol with heat to provide enantiomerically pure dihydropyridines of general formula (123) and (124). Scheme 27 represents one technique for separation of dihydropyridine racamates. Racemates may also be separated via chiral column chromatography before treatment with acetic anhydride.
The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incorporated by reference.